Many pathological conditions, including metabolic syndrome, impaired glucose tolerance, hepatitis, pulmonary emphysema, chronic obstructive pulmonary disease, prostatitis, benign prostatic hyperplasia, hypogonadism, testicular failure, asthenospermia, are accompanied by a decrease in functional activity and structural damage of affected organs.
Metabolic syndrome is a pathological symptom-complex that includes various metabolic and hormonal disorders. Diagnosis “metabolic syndrome” is made in the presence of central obesity and at least two of the following factors: 1) an increase in the triglyceride level≥150 mg/dl (1.7 mM/1), 2) a reduce in the high-density lipoprotein (HDL) cholesterol level<40 mg/dl (1.03 mM/1) (men), <50 mg/dl (1.29 mM/1) (women), 3) arterial hypertension (arterial pressure (AP)≥130/85 mm Hg or normal AP controlled by hypotensive medications), and 4) an increase in the plasma glucose level≥100 mg/dl (5.6 mM/1). Today, metabolic syndrome is approximately equally common in men and women; its frequency, for example, in the USA reaches 39% [Flegal K. M., Carroll M. D., Ogden C. L., et al. Prevalence and trends in obesity among US adults, 1999-2000//The Journal of the American Medical Association. 2002. Vol. 288(14). P. 1723-1727].
According to data of different authors, hypogonadism (testosterone deficiency) is revealed in 30-50% of men with obesity and other symptoms of metabolic syndrome (testosterone deficiency). Many researchers have found not only a high prevalence of hypogonadism in men with metabolic syndrome, but also a relationship between the total testosterone plasma level and symptoms of metabolic syndrome. There are reports on both a relationship between overweight and low testosterone levels and a relationship of insulin resistance and a decreased testosterone level in the blood serum of men with obesity [Svartberg J., von Mühlen D., Sundsfjord J., et al. Waist circumference and testosterone levels in community dwelling men. The Tromsø study//European Journal of Epidemiology. 2004. Vol. 19(7). P. 657-667]. A reduction in the serum testosterone level in metabolic syndrome and insulin resistance in men is a result of impaired functional activity of testicular tissue. In accordance with this, the methods of regeneration of testicular tissue, intended for the treatment of hypogonadism both as an independent disease and as a disease associated with metabolic syndrome are of current importance.
An adult pancreas contains approximately 109 cells. Normally worn-out β-cells are constantly replaced by new ones that proliferate in the pancreas (Minami K., Seino S. Current status of regeneration of pancreatic β-cells. Journal of Diabetes investigation. Volume 4, Issue 2. pages 131-141 March 2013). In various pancreatic disorders, such as autoimmune or toxic disorders, β-cells of islets of Langerhans are first characterized by a reduced functional activity, which manifests itself in a decrease in insulin production, and in later stages, they die. Explicit symptoms of pancreatic tissue damage appear when more than 90% of β-cells are destroyed, insulin deficiency becomes permanent, leading to complete dependence on insulin injected from the outside.
Insulin therapy does not allow the accuracy of glycemic regulation that is provided when the islets of Langerhans function normally. There are still attempts to treat damaged pancreas with transplantation of the whole organ, islets of Langerhans, and β-cells. However, transplantation is not always successful (transplant rejection occurs frequently). In successful transplantation, a patient subsequently will continuously need immunosuppressant drugs.
Another problem is impaired glucose tolerance. It is an impaired metabolic response to endogenous or exogenous insulin. This condition leads to an increased insulin plasma concentration compared to the physiological values for the existing glucose concentration. Impaired glucose tolerance in muscle, adipose, and liver tissue is most clinically significant. Impaired tolerance to glucose in the muscle tissue leads to a decrease in the uptake of glucose from the blood into myocytes and its utilization in muscle cells, and in the adipose tissue it manifests itself in resistance to the anti-lipolytic action of insulin, resulting in the accumulation of free fatty acids (FFA) and glycerol. FFAs enter the liver, where they become the main source for the formation of very-low-density atherogenic lipoproteins (VLDAL). Impaired glucose tolerance in the liver tissue is characterized by a decreased synthesis of glycogen and activation of the decomposition of glycogen to glucose (glycogenolysis) and de novo synthesis of glucose from amino acids, lactate, pyruvate, and glycerol (gluconeogenesis). Thus, the treatment of impaired glucose tolerance in tissues makes it possible to restore functional activity of the tissues.
The liver is a vital body gland. It performs about 500 unique functions that support the processes of digestion, inactivation of toxic substances, synthesis of blood coagulation components, metabolism of proteins, amino acids, fats, carbohydrates, nucleic acids, vitamins, trace elements, and the like. The liver tissue is often damaged by chemical, microbial, traumatic, pharmaceutical and other adverse factors. This leads to a decrease in the number of functional hepatocytes. Chronic hepatitis of various etiologies can last for many years, and is often diagnosed in the later stages of the disease, when the likelihood of developing cirrhosis and chronic liver failure increases dramatically [Jung Y1, Witek R P, Syn W K. Signals from dying hepatocytes trigger growth of liver progenitors//Gut.—2010.—Vol. 5. P. 655-65].
The known hepatoprotectors are: Essentiale, lipoic acid, Sirepar, and α-tocopherol. However, these drugs cannot completely protect or restore the impaired functions of membranes, mitochondria and other structures of hepatocytes since any of them has an action only on separate stages of the pathogenesis of hepatitis. In this connection, complex therapy involves the use of hemoprotectors. However, such an approach to the treatment of hepatitis is dangerous because of the interaction of drugs due to polypharmacy and complication of the disease process itself. In addition, almost all drugs of this group have side effects limiting their use. In view of the above, the development of methods that can effectively stimulate liver regeneration remains very actual.
One of the most frequent clinic pathologies of male infertility is an inflammatory disease of the sex accessory glands.
The inflammatory diseases of the sex accessory glands include diseases of the prostate gland associated with inflammation, such as acute bacterial prostatitis, chronic bacterial prostatitis, BPH (benign prostatic hyperplasia), as well as inflammation of the seminal vesicles, such as acute or chronic vesiculitis. Diseases of the prostate gland also include chronic abacterial prostatitis, chronic non-inflammatory prostatitis and category 3B prostatitis [Ludwig M, Vidal A, Diemer Th, Pabst W, Failing K, Weidner W. Chronic prostatitis/chronic pelvic pain syndrome: seminal markers of inflammation.//World J Urol. 2003. Vol. 21, N 2. P. 82-85].
The above pathologies occur in 40-70% of men. Forty percent of men with pathospermia has chronic prostatitis, which in 80% of cases is abacterial (Benway B. M., Moon T. D.//Urol Clin North Am 2008 February; 35(1):23-32).
It should be noted that chronic inflammation of the prostate gland is very often associated with benign prostatic hyperplasia (BPH). BPH-associated hyperprolactinemia leads to erectile insufficiency, oligospermia. This, of course, reduces male reproductive potential [Johri A. M., Heaton J. P., Morales A. Severe erectile dysfunction is a marker for hyperprolactinemia//Int J Import Res. 2001. Vol. 13 N3. P. 176-82].
Many aspects of prostate disease affect the ejaculate quality since the prostate gland releases the factors supporting, above all, sperm motility. In this regard, correlative testicular failure (secondary infertility) is revealed during the development of prostate disease. Thus, the treatment of prostate gland diseases favorably affects male fertility.
Currently, the drugs that have a positive effect on the factors associated with the course of chronic abacterial prostatitis and BPH include plant extracts—Prostamol Uno [Bayane C. W., Ross M., Donnelly F., Habib F. K.//J. Urol. 2000. Vol. 164, N3, Pt.1. P. 876-881]. However, they are not always quite effective.
The inhibition of the formation of androgens (hypogonadism) also results in a reduction in male fertility [Dohie G. R., Diemer A., Giwerman A., Jungwith A., Kora Z., Kraus C. Man Infertility, European Association of Urology 2014. 7].
Male hypogonadism is now found in 4-5 million people. Hypogonadotropic hypogonadism (or secondary hypogonadism) is caused by gonadotropin deficiency. Primary hypogonadism is caused by testicular (testicle) dysfunction. Its non-hereditary forms (acquired hypogonadotropic hypogonadism) may be a result of external actions, administration of drugs (anabolic steroids, metoclopramide, phenotiazid, narcotic drugs, etc.), and radiation therapy [Filicori M. Endocrine basis of reproductive function.—Bologna: Monduzzi Editore, 2000.—R 605; Meczekalski B., Tonetti A., Monteleone R. et al. Hypothalamic amenorrhea with normal body weight: ACTH, allopregnanolone and cortisol responses to corticotrophin—releasing hormone test//Eur. J. Endocrinol.—2000.—V.142.—R. 280-285].
Patients with secondary hypogonadism are prescribed testosterone [Dohie G. R., Diemer A., Giwerman A., Jungwith A., Kora Z., Kraus C. Man Infertility, European Association of Urology 2014, p. 35]. However, testosterone has many contraindications and side effects.
The known drug Tribestan (manufacturer Sopharma (Bulgaria)) stimulates production of testosterone in men and increases sperm motility, but the effectiveness of this drug is not always high.
Hypogonadism caused by sex gland pathology (hypergonadotropic hypogonadism or testicular failure) refers to the most common form of a reduction in male fertility [Dohie G. R., Diemer A., Giwerman A., Jungwith A., Kora Z., Kraus C. Man Infertility, European Association of Urology 2014, p. 8].
The action of exogenous factors, such as drugs, including cytostatic agents, radiation, temperature increase, is one of the causes of its appearance. Long-term reduction in the spermatogenesis productivity, down to its total arrest, is a consequence of a damage affected type A spermatogonia. Restoration of spermatogenesis after damage is possible only owing to these cells. They do not lose the specificity of the sperm cells because they have irreversibly identified themselves as precursors of spermatogenesis, and, like stem cells, have the colony-formation ability. These cells constitute a deep reserve of the regenerative capacity of spermatogenic tissue.
It is known that the proliferative potential of spermatogenesis can be restored by transplantation of spermatogenic cells. The drug therapy of hypergonadotropic hypogonadism is recommended with testosterone. It stimulates the final phase of spermatomeiosis, i.e. postmitotic division, thereby leading to an increase in the number of spermatocytes and an increase in the spermatogenesis productivity by stimulating its final phase. A disadvantage of this agent is its inefficiency to stimulate spermatogonia, which, as known, are divided mitotically.
In the pharmaceutical market there are no drugs for the treatment of male infertility caused by the depletion of a deep reserve of the regenerative capacity of spermatogenic tissue, and the recovery of the number of committed colony-forming spermatogenic cells. The agent for recovery of male fertility in testicular insufficiency caused by stem cell damage, according to the present invention, has no analogues among the existing therapeutic agents for the treatment of this pathology.
In many cases, a reduction in male fertility is caused by deterioration of sperm quality. The most common ejaculate pathology is asthenospermia (Kao S. H. et. al. Increase of oxidative stress in human sperm with lower motility. Fertil. and Steril. 2008; 89: 5: 1183-1190). Asthenospermia-type failure of spermatogenesis is considered as a separate nosological form. It is a consequence of age-related changes, smoking, inflammation, dyshormonal disorders, and exposure to toxic substances and high temperatures. The treatment of asthenospermia depends on the causes of its appearance. However, these hormonal drugs cause serious side effects and have contraindications.
It is recommended to treat asthenospermia with Speman medication that stimulates spermatogenesis and increases sperm motility. The drug is expensive, consists of a complex composition of medicinal herbs that grow in different countries of the world and have limited raw stock. As a drawback, it should be noted that it is not highly effective.
Pulmonary emphysema, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are severe multifactorial pulmonary disorders characterized by chronic and progressive course in elderly patients (predominantly in men). The clinical pattern and pathogenesis of COPD differs from IPF. The cause of the slightly reversible and progressive airway obstruction in COPD is airway inflammation and emphysematous enlargement of alveoli and bronchioles [Hogg J C, Timens W: The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol 2009, 4:435-459], while the restriction of pulmonary function in IPF is caused by the development of interstitial fibrosis and the formation of “honeycomb” lung [American Thoracic Society: Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000, 161:646-664]. The prevalence of these two lung diseases is completely different. However, every year the incidence and prevalence of IPF is steadily increasing, which is connected, inter alia, with an improvement of diagnostic tools. In turn, the prevalence of COPD has always been very high. The disease is associated to a large extent with inhalation of harmful external substances (mainly due to smoking).
Despite a sufficiently large number of experimental and clinical studies, the understanding of the pathogenesis of pulmonary emphysema and COPD is limited: there are no recognized effective approaches to the treatment of this disease. The existing set of drugs for IPF is limited to glucocorticoids, cyclophosphamide, immunosuppressants, and anticoagulants, is aimed at treating complications, and is essentially a maintenance therapy. Currently, only such a therapeutic agent as Pirfenidone has been approved for the treatment of IPF. Meanwhile, in clinical trials, Pirfenidone did not show an expected high antifibrotic activity at the developed stage of the disease. In addition, the drug has many side effects and requires high doses.
The development of IPF, COPD, malignant neoplasms and many other chronic diseases is associated with a sharp loss of body weight. The greatest danger is the extreme degree of emaciation—cachexia. Clinically, cachexia is manifested by excessive weight loss associated with the ongoing disease process, usually with disproportionate skeletal muscle atrophy.
Diseases leading to cachexia are characterized by a decrease in the functional activity of testicular tissue and, as a consequence, a decrease in the level of testosterone. Testosterone stimulates myoblasts and increases the number of satellite cells, thereby contributing to the protein synthesis and recovery of damaged muscles [Bhasin S., Taylor W. E., Singh R. et al. The mechanisms of androgen effects on body composition: mesenchymal pluripotent cell as the target of androgen action. J Gerontol Med Sci 2003; 58A:M1103-1110]. Testosterone also suppresses the synthesis of proinflammatory cytokines IL-1, IL-6, TNFα and stimulates the production of anti-inflammatory cytokine IL-10. An extreme degree of emaciation in various diseases is associated with an inflammation. Inflammatory mediators prevent the synthesis of muscle proteins in cachexia, and are involved in lipolysis and beta-oxidation of fatty acids [Ryden M., Arvidsson E., Blomqvist L., Perbeck L., Dicker A., Arner P. Targets for TNF-alpha-induced lipolysis in human adipocytes. Biochem Biophys Res Commun 2004; 318:168-175].
Unfortunately, there is still no single recognized approach to the treatment of cachexia. Numerous attempts have been made to correct this condition. Therapy of patients with severe weight loss includes medications of testosterone, growth hormones (somatropin), appetite stimulants (serotonin antagonists, progestogens, dronabinol), and inhibitors of gluconeogenesis (hydrazine sulfate), but their effectiveness is not sufficient.
Thus, an object of the present invention is to provide an agent for regeneration and recovery of diminished functions of tissues. Such an agent will, in particular, promote the treatment of glucose tolerance disorders, hepatitis, pulmonary emphysema, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cachexia, and will promote the recovery of male reproductive function, and will overcome the drawbacks of the known agents described above.
More specifically, a first object of the present invention is to provide an agent that promotes regeneration of tissues, in particular pancreatic, liver, lung, testicular, prostate, and muscle tissues. In particular, the agent according to the invention should promote the regeneration of testicular tissue and prostate tissue.
Another object of the present invention is to provide an agent for lowering the blood glucose level increased, in particular, due to pathological conditions such as metabolic syndrome or impaired glucose tolerance.
One more object of the present invention is to provide an agent for recovery of liver function reduced in particular due to pathological conditions, such as viral chronic hepatitis.
It is another object of the present invention to provide an agent for normalizing a reduced male sexual activity caused, in particular, by such pathologies as hypogonadism, correlative testicular failure, and testicular failure.
A further object of the present invention is to provide an agent for recovery of spermatogenesis (including sperm motility) reduced, in particular, due to such pathologies as metabolic syndrome, prostatitis, hypogonadism, asthenospermia, testicular failure, and other diseases.
One more object of the present invention is to provide an agent for recovery of a disturbed histoarchitectonics and functions of pulmonary tissue, which is caused, in particular, by such pathologies as emphysema, idiopathic lung fibrosis and chronic obstructive pulmonary disease.
Another object of the present invention is to provide an agent for recovery of liver structure and function.
It is a next object of the present invention to provide an agent for recovery of pancreas structure and function affected by such diseases as metabolic syndrome and impaired glucose tolerance.
These objects are achieved due to the use of a Treamid-based drug as an agent for the treatment and/or prevention of the above pathological conditions. Said agent is a bisamide derivative of dicarboxylic acid of formula (I):

or a pharmaceutically acceptable salt thereof.
This compound is described in RU301116822 (published on Oct. 20, 2014) relating to novel compounds suitable for use as metal chelators, including for the treatment of diseases associated with metal chelating activity.
The inventor has discovered, at first, that Treamid is able to efficiently regenerate tissues and restore their diminished functions; this, in particular, concerns the male reproductive system tissues. Treamid reduces the severity of morphological changes in the prostate gland in abacterial prostatitis and BPH, restores sperm motility, enhances sex drive and copulatory activity, which, in combination, leads to the recovery of male reproductive function.